Skeletal erosion has been found to represent an independent prognostic indicator

Published January 24, 2018

Skeletal erosion has been found to represent an independent prognostic indicator in patients with advanced stages of chronic lymphocytic leukaemia (CLL). of leukemic clone. Introduction B-cell chronic lymphocytic leukaemia (CLL) is the most frequent leukaemia in western countries1,2. It mainly occurs in the KN-62 elderly, with 85C90% of patients being diagnosed after the age of 503. Almost one third of CLL patients do not require any treatment during the entire disease course4,5. However, in the majority of patients CLL aggressiveness increases at a variable time after diagnosis, because of the combination of antiapoptotic mechanisms5 and enhanced proliferating activity6C10 . Factors triggering this progression are still not fully clarified KN-62 and no treatment has shown capability to halt disease progression in the asymptomatic phase11,12. However, there is accumulating evidence that the TNF superfamily member Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) and its receptor RANK do play a role in CLL clone upkeep and in the progression of other B-cell related hematologic malignancies13C18. This pathway is indeed crucial in the immune systems physiological development, as mice lacking RANK show absent lymph node development and impaired B-Cell differentiation19. In CLL, the recognized abundance of surface RANKL is often paralleled by an aberrant RANK KN-62 expression14C16. On one side this phenomenon leads to an upregulation of interleukin-8 expression/release improving clone survival and expansion14. On the other hand, the capability of this same axis to promote osteoclast commitment in circulating monocytes enhances bone reabsorption possibly leading to the release of a variety of growth factors into the bone microenvironment as recognized in multiple myeloma and bone metastases15,20,21. Using a dedicated software, capable of quantifying volumes of compact (CBV) and trabecular bone (IBV) from X-ray CT slices22C24, we already documented a selective erosion of compact bone, which managed to predict patients disease-specific survival, providing prognostic information independent from the commonly employed biomarkers23. Similarly, Lagenberg at CT2 (Fig.?3D) and was visually Slc4a1 confirmed by high-resolution CT images that provided a description of spatial distribution of bone tissue within the whole femur in 3D (Fig.?3E) and 2D reconstruction (Fig.?3F). Figure 3 Panel A displays hematoxylin-eosin eosin staining of bone and bone marrow biopsy in a sham mouse with magnification related to the green insert. Panel B displays the same analysis in an untreated xenograft model KN-62 (relative to the red insert): a high number … Overall, CLL was associated with an increase in IBV/SV with respect to sham group at CT2 (7.2%??1.1% vs 4.2??1.3%, respectively, p?0.001) (Fig.?4A). In untreated CLL mice, femur IBV/SV ratio did not significantly change and remained higher than controls at CT3 (Fig.?4A). By contrast, Denosumab induced an apparent normalization of bone structure reducing IBV/SV ratio to values significantly lower with respect to untreated mice (Fig.?4B) and similar to the value reached by control group during the three weeks of aging (Fig.?4A). Figure 4 Panel A reports column chart of % IBV/SV ratio in control mice, CLL untreated mice (CLL no treatment) and CLL Denosumab ones. KN-62 White columns indicate bone erosion at CT2 (four weeks after CLL cells administration) while grey columns report the same variable ... The role of human CLL in bone erosion was further confirmed by the observation that, one week after the last treatment, number of neoplastic B-cells detected in BM and spleens was significantly higher in untreated xenograft models with respect to those treated with.